Processes for the production of 19-nor-delta4-[9beta], [10alpha]-androstenes and intermediates



United States Patent 3,138,617 PROCESSES FOR THE PRODUCTION OF 19-N0R-A[9 3],[10a]-ANDROSTENES AND lNTERlVIEDIATES Gerard Nomine and AndrePierdet, Noisy-le Sec, Robert B'ucourt, Villiers le Bel, and JeanTessier, Paris, France, assignors,- by mesne assignments, toRoussel-UCLAF S.A., Paris, France, a corporation of France No Drawing.Filed May 22, 1961, Ser. No. 111,499 Claims priority, application-FranceAug. 27, 1959 15 Claims. (Cl. 260--345.2)

The present invention relates to new 19-nor-steroids, and in particularto 19-nor-A -[9fl],[10a]-androsten-17B- ol-3-one and its esters, to thepreparation of the said 19- nor-steroids and to the intermediatecompounds utilized in the synthesis of said l9-nor-steroids and inparticular to 3-alkoxy-3 -methyl-4-oxa-19-nor-A [913 -androsten- 175-01and its esters.

More particularly it relates to l9-nor-steroids of the Formula HI:

wherein R represents a radical selected from the group consisting ofhydrogen, lower alkyl and the acyl radical of an organic carboxylic acidhaving from one to eighteen carbon atoms.

It is a further object of the invention to develop processes for thepreparation of the new l9-nor-steroids.

Another object of the invention is the preparation of the intermediateoxa steroids of the formula:

wherein R represents a radical selected from the group consisting ofhydrogen, lower alkyl and the acyl radical of an organic carboxylic acidhaving from one to eighteen carbon atoms and R represents a lower alkylgroup.

These and other objects of the invention will become more apparent asthe description thereof proceeds.

3,138,617 Patented June 23, 1964 We have found that 19-nor-steroids ofthe Formula HI:

10 III wherein R represents hydrogen, a lower alkyl radical and the acylradical of an organic carboxylic acid having one to eighteen carbonatoms, can be produced starting from compounds of the Formula 1:

0 ergo wherein R has the above-assigned meanings by catalytichydrogenation in the presence of a lower alkanol to give compounds oftheFormula H:

, wherein R has the above-assigned meaning and R represents a loweralkyl group. These latter compounds are subject to the action of astrong mineral acid in the presence of an organic solvent to produce the19-norsteroids of Formula III.

. 19-nor-steroids of Formula'III can also be produced by cyclizingcompounds of the Formula IA:

wherein R has the above-assigned meaning, at elevated temperatures withthe aid of an alkaline dehydrating agent and-separating19-nor-steroidsof Formula HI' from the l9-nor-testosterones, alsoproduced, by chroma tography. The production of 19-nor-testoster'ones bythis process is the subject matter of U.S: patent application S.N.36,172, filed-June 15,1960, now abandoned. This application is acontinuation-in-part of said S.N. 36,172.

The present invention with reference to the preparation of oxa steroidsof Formula II, is based in particular on the unexpected observation thathydrogenation of compounds of the partial formula:

in an hydroxylated solvent such as a lower alkanol leads to a pyraniccompound of the partial formula:

in which R represents the lower alkyl radical of the hydroxylatedsolvent utilized and where the hydrogen added on the 9 carbon atom is inthe desired orientation.

The process of preparation of oxa steroids of Formula H is essentiallycharacterized in that a A -3-methyl-7- ox-8-(3 oxobutyl) 3,4[3-hydroxy-cyclopentano-(2, 1')]-octahydronaphthalene, whose hydroxylgroup in the 3' position may be free or blocked, is hydrogenated in thepresence of a catalyst such as palladized carbon black in solution in anhydroxylated solvent, such as a lower alkanol, in an acidic media and a4-oxa-[9,B]-l9-norsteroid, of Formula II is isolated.

The solvent in which the hydrogenation is effected is preferentiallyethanol, which leads to a compound of Formula H ethoxylated in the 3position (R =C H The media is, of preference, Weakly acidic and theproper degree of acidity can be obtained by use of a catalyst preparedin an acidic media then washed with water. The small amount of acidwhich this catalyst retains despite the Washing 'sufiices to adjust thepH of the hydrogenation solution to between 4 and 5.

The preparation of the starting racernic or optically active A-3-methy1-7-oxo-8-(3'-oxobutyl)-3,4-[3'-acyloxy-cyclopentano-(2',1')]octahydronaphthalene compounds of the Formula I:

wherein R represents a member selected from the group consisting ofhydrogen, lower alkyl and the acyl radical of an organic carboxylic acidhaving from 1 to 18 carbon atoms is described in the copending,commonly-assigned US. patent No. 3,019,252.

Among the starting compounds it is preferable to use one whose hydroxylin the 3' position is blocked either in the form of an easilycrystallizable ester, such as the benzoate, hexahydrobenzoate,halobenzoates, nitrobenzoates, naphthoate, phthalates, pivalate,cycloalkylacetates, etc. or in the form of an ether such as the ethyl,dihydro or tetrahydropyranyl ethers.

The process of the invention is advantageously executed by using as thestarting compound A -3-methyl-7-oxo- 8 (3 oxobutyl) 3,4 [3 benzyloxycyclopentano- (2', 1)]octahydronaphthalene (compound I wherein Ac=C HCO). However, other esters of organic carboxylic acids having from 1 to18 carbon atoms, such as the alkanoates and alkenoates, for example, theacetate, the trimethylacetate, the propionate, the4,4-dimethylpent-anoate, the IO-undecenoate; the cycloalkyl-alk-anoates,for example, the fi-cyclopentyl-propionate; the arylalkanoates, forexample, the phenyl-propionate; the the cycloalkanoates, for example,the hexahydrobenzoate, the hexahydroterephthalate and otherphenyl-carboxylic acids '4 may also be used without departing from thescope of the invention.

In the case where the obtention of the pyranic compound ]1 in the formof the free alcohol is desired, it is possible to start fromnon-esterified compound I. However, it is much more advantageous to formthe pyranic compound II whose hydroxyl is blocked and to subsequentlysaponify it. The yields are superior since the pyranic ring is resistantto thealkaline attack.

The invention extends, as has already been indicated, to the process ofusing the oxa steroids in the synthesis of 19-nor-steroids, epimeric inthe 9 and 10 positions, with the products of the natural series by theaction of a strong mineral acid on said oxa steroids.

The action of a strong mineral acid on the pyranic compounds of FormulaII opens the pyranic ring with subsequent aldolization and simultaneousdehydration to give a ring with a ketone function in the 3 position anda double bond in the 4, 5 position.

In order to cyclize the pyranic compounds of Formula II, hydrochloricacid is advantageously utilized. The reaction is conductedpreferentially in the presence of an oxygenated organic polar solventsuch as dioxane or acetic acid. It is best to maintain the reactiontemperature constant and below 25 C.

One method of advantageous execution, if the compound of Formula II isesterified, consists in saponifying the pyranic compound II andthereafter cyclizing it.

According to another mode of execution, it is also possible to cyclize apyranic compound H, whose hydroxyl in the 17 position is blocked, intothe 19-nor-steroid and, thereafter, to proceed to the saponificationstep in order to obtain a 19-nor-steroid of Formula III having a 17-hydroxyl group.

After saponification of the 19-nor-steroids thus obtained, they areobviously easily re-esterified by all esterifying derivatives of organicor mineral acids.

The invention includes also the different esters of 19-nor-[9fi],[10a]-steroids, obtained by the present process. Thesecompounds have an interesting pharmacodynamic activity and possessparticularly an antihypophysial or anabolising action.

Table I represents a flow diagram of the above reaction.

TABLE I R and R have the above-assigned meanings.

As disclosed above, another method of obtaining l9-I10I-[9}3],[10a]-Sl810id$ of Formula III is the isolation of thesecompounds as secondary productsin the cyclization of3-methyl-7-oxo-8-(3-oxobutyl)-3,4-[3'-acyloxycyclopentano-(2,1)-decahydronaphthalene compounds of Formula IA at elevated temperatureswith the aid of alkaline dehydrating agents such as alkali metal loweralkanolates at elevated temperatures in the presence of a lower alkanolcorresponding to the alkanolate used. After isolation of the19-nor-testosterones' as taught in S.N. 36,172 by chromatography oversilica gel with-elution with methylene chloride containing increasingamounts of acetone up to 6% acetone, the desired 19-nor-[9fi], [100a]-steroids ofFormula III are isolated by further elution with methylenechloride containing 6%' acetone.

The raw product thus obtained ispurified by fractionalrecrystallization.v

The following examples, which are given purely for illustration, arenon-limitative in character and will make the invention'betterunderstood to one skilled in the art. The melting points areinstantaneous melting points determined on a Maquenne block. Thetemperatures are given in degrees centigrade.

Example I.-Preparation of 3-Eth0xy-3-Methyl-4-Oxa-l9- Nor A500) [9,6]Androsten -117fi 01 (Compound H; and R1:C2H5) 0.68 gramof activatedcarbon, 68 cc. of ethanol and 0.34 cc. of an aqueoushydrochloric acidsolution containing 33% palladium chloride were agitated under hydrogenfor a period of 30 minutes. The catalyst, so prepared, wasvacuumfiltered and washed with water. It was then washed with ethanol andplaced in suspension in 270 cc. of ethanol in which 3' grams of A -3-methyl 7 oxo 8 (3 oxobutyl) 3,4 [3' benzoyloxy cyclopentano (2',l')]octahydronaphthalene (I) had previously been dissolved. The mixture wasagitated in an atmosphere of hydrogen for a period of 28 hours at 20.decantation of the mother liquors and subjected to four successiveextractions, each time with 20 cc. aliquots of boiling ethanol; Thealcoholic extracts were combined and added to the mother liquor. Theliquors were concentrated to 30-35 cc. by distillation under vacuum.Thereafter, the liquors were cooled to C. and the precipitate wasrecovered which was vacuum filtered and Washed with ethanol. 1.6 gramsof 3-ethoXy-3-methyl- 1'75 benzoyloxy 4 -'oxa 19 nor- N410) [9,81androstene (Compound II; R=C H CO and R =C H were obtained.

. It was possible to obtain another fraction of this compound bytreatment of the mother liquors with T reagent. A total yield of 1.73-grams, being 52% of theoretical, ofa compound having a melting point of190 C. and a" specific rotation [a] =+36 (c'.=0.5% in benzene) wasobtained.

The product occurs in the form of colorless needles, is slightly solublein most organic solvents and insoluble in water.

Analysis.C H O molecular weight-=424.55. Ca1- culated: C, 76.38%; H,8.54%. Found: C, 76.4%; H, 8.6%.

Ultraviolet spectra (ethanol);

A max. at 229 m 15:13 800 A max. at 273 m,u, e=280 Infra-red spectra(carbondi-sulfide):

Band at 5.94 1.

This product has not been described in the literature. ,The startingcompound, Compound I, is prepared according" to the process described inUS. Patent No. 3,019,252.

The catalyst was next separated by OXA 1'9 NOR A [913] ANDROSTEN 17B 0L"(COMPOUND II R=H AND R1: CaHs).

1.86 grams of 3-methyl 3-ethoxy-17,!3-benzoyloxy-4-oxa- 19 nor A [9131-androstene (Compound II where R'=C H CO and R =C H5) were heated toreflux for a period of an hour and a half in 186 cc. of 1 N alcoholicpotassium hydroxide containing 10% water. The mixture was thenconcentrated to a volume of 30 40 cc. by heating under vacuum, thendiluted with 300 to 400 cc. of water and the precipitate formed wasfiltered. This precipitate was vacuum filtered and washed with water.1.31 grams of 3-methyl-3-ethoxy-4-oxa-l9-nor-A -[9,8]- androsten-l7 3-ol(Compound II Where R=H, R =C H was thus obtained, being a yield of 94%.Melting point: 141 C.

On recrystallization from isopropyl ether, the melting point was raisedto 142 C. andthe specific rotation was [a] ='-43.3 (c. =0.5%-inbenzene).

Application of 3 alkoxy 3 methyl 4 oxa-19-nor- M -[9B]-androsten-17fl-olwhose hydroxyl group in the 17 position is free or blocked, of FormulaII, to the preparation of 19'-nor-steroids having an inverse config--uration in the 9 and 10 positions is shown as follows:

Example Il.Preparati0n of l9-N0r-A [-95] [1004] -An-'dr0sten-17/3-0l-3-0ne (Compound III, R=H) maintaining the temperature at20 C. The reaction mixture was then poured into cc. of 7% sodiumcarbonate solution. A white crystalline precipitate appeared which wasseparated by filtration, vacuum filtered, washed until neutral withwater and then dried under vacuum over phosphoric acid.

0.320. gm. of 19-nor-A [9 3],[1'0a]-androsten-17,8-ol- 3 -one (compoundIII, R=H)- were obtained, being a yield of 94%. The raw product whichwas obtained melted at 212 C.

I By recrystallization from hot acetone after cooling there was obtained0.222 gram of a compound which crystallized in small prismatic rods andmelted at 222- 223 C.

The compound was very soluble in chloroform, soluble in ether, slightlysoluble in acetone and insoluble in water.

Infra-red spectra (in chloroform):

Shows presence of bands characteristic of hydroxyl groups and 3-keto-A-conjugated ketones.

Example [Hr -Preparation of J9 N0r-A -'[9/3],[10a]-Andr0sten-17 3-Ol3-One by the Intermediate 17-Benz0ate Ester 0.415 gram of3-ethoxy-3-methyl-17B-benzoyloxy-4 oxa 9- nor A [9B]-andro'stene (II,R=C H CO, R =C H were dissolved in 8.3 cc. of acetic acid under anatmosphere of nitrogen, 0.6 cc. of concentrated hydrochloric acid wereadded and the reaction mixture was allowed to stand for a period of 20hours at a temperature of 20 C. 40 cc. of a 5% sodium carbonate solutionwas then added to the reaction mixture which was' agitated. Theprecipitated product was then extracted with ether. The ethereal phaseswere decanted, combined, washed with v'vater, dried and evaporated todryness under vacuum. After recrystallization from ether 0.30 gram(being 80%) of l7B-benzoyloxy-9-nor-.

A -[9B] lot]-androsten-3-one (compound HI;

R: C H CO) was obtained having a melting point of 160 C. and a specificrotation [u] -=+Z (c.=0.5% in methanol).

The product had the form of prismatic colorless needles, was soluble inmost of the usual organic solvents and particularly in methanol andethanol.

Analysis.-C H O molecular weight=378.5. Calculated: C, 79.32%; H, 7.99%.Found: C, 79.2%; H, 7.9%.

The infrared spectra confirmed the presence of a band corresponding toan ethenically conjugated ketone, similar to that of 19-nor-steroidspossessing the ketonic system conjugated in the 3-4 position. Themeasure of the rotatory dispersion gave a curve antipodial to that ofl9-nor-testosterone.

The compound is not described in the literature.

Saponification of the hereabove product by an alkaline agent furnished19-nor-A -[9/3],[l0a]-androsten- 17,8-01-3-one, melting at 223 C.(compound III, R=H) identical to the product described in Example II.

Example I V.Preparation of 19-N0r-A -[9fl],[10a1-Andr0sten-17B-Ol-3-One(HI; R=H) by Cyclization of 3 Methyl 7 0x0 8 (3 Oxobutyl) 3,4 [3'Benzoyloxy Cyclopentano (2,1')] Decahydronaphthalene 1 gram of 3 methyl7-oxo 8-(3-oxobutyl)-3,4-[3- benzoyloxy cyclopentano (2',1)]decahydronaphthalene (IA, R=C H CO) was dissolved in cc. of methanolunder an atmosphere of nitrogen. Compound IA was obtained byhydrogenation of A -3-methyl-7- oxo 8 (3 oxobutyl) 3,4 [3 benzoyloxycyclopentano-(2,1')]-octahydronaphthalene (I, R=C H CO), melting point117 C., specific rotation [a] =+43 (c.=l% in methanol), according to theprocess described in US. patent application S.N. 36,172.

To the methanolic solution of the starting compound there were added26.2 cc. of a 1 N methanolic potassium hydroxide solution and thereaction mixture was heated to reflux under nitrogen for a period of 2hours. The reaction mixture was then evaporated to dryness under vacuum,added to water and extracted with ether. The ether extracts werecombined, washed, with water, dried over sodium sulfate, filtered andthen evaporated to dryness under vacuum. 0.500 gram of a yellow resinwas obtained which was subjected to chromatography over silica gel (40grams) with elution, first with pure methylene chloride, then withmethylene chloride containing an increasing percentage of acetone. Theelution was effected by fractions of 40 cc. of solvent. The first ninefractions with methylene chloride containing 6% acetone furnished 19-nor-testosterone. The following fourteen elution fractions withmethylene chloride containing 6% acetone gave, after evaporation ofsolvent, 450 mg. of the 9,6,10a-epimer of 19-nor-testosterone. Theselast fractions were chromatographed a second time under the sameconditions but by fractions of 30 cc. of solvent. The elution fractionswith methylene chloride containing 6% acetone were isolated andevaporated to dryness. The residue crystallized spontaneously and thedesired 10a isomer, 19 nor A -[9 3],[10a] -androsten- 17fi-ol-3-one(I11; R=H) was recovered and purified by recrystallization from hotacetone. The product obtained melted at 223 C. and had a specificrotation [a] =-86.3 (c.=1% in ethanol).

The product was very soluble in chloroform, soluble in benzene, acetone,alcohol and ethyl ether, slightly soluble in isopropyl ether andinsoluble in water and in dilute aqueous alkalis.

Analysis.-C H O molecular weight=274.4. Calculated: C, 78.79%; H, 9.55%.9.7%.

Ultraviolet spectra (in ethanol):

)t at 242 III/L, e: 16 200 This product is not described in theliterature. It will be understood that the invention is not limited tothe specific modes of execution described above. Par- Found: C, 79.0%;H,

ticularly, it is evident to one skilled in the art that equiva lenttechniques may be employed, such as varying the temperatures, the natureof the solvents, or the ester of the organic carboxylic acid and thelower alkanol solvent, without departing from the spirit of theinvention or the scope of the appended claims.

We claim:

1. An oXa-steroid of the formula:

wherein R represents a radical selected from the group consisting ofhydrogen, lower alkyl, dihydropyranyl, tetrahydropyranyl and the acylradical of an organic carboxylic acid having from one to eighteen carbonatoms selected from the group consisting of alkanoic acids, alkenoicacids, cycloalkyl-alkanoic acids, phenylalkanoic acids, cycloalkanoicacids, phenylcarboxylic acids, halophenylcarboxylic acids,nitrophenylcarboxylic acids and naphthoic acid and R represents a loweralkyl group, which comprises the steps of hydrogenating a compound ofthe formula:

CH3 OR 0 ClO wherein R has the above-assigned meanings in the presenceof a catalyst and a lower alkanol solvent in an acidic media andrecovering said oxa steroid.

5. The process of claim 4 wherein said lower alkanol solvent is ethanol.

6. The process of claim 4 wherein said catalyst is palladized carbonblack prepared in an acidic media.

7. The process of claim 4 wherein the pH of said acidic media is between4 and 5.

8. The process of producing 3-ethoxy-3-methyl-4-oxa- 19-nor-A-[9,8]-androsten-17Bol which comprises the steps of hydrogenating A -3methyl 7 oxo 8 (3- oxobutyl) 3,4 [3'-benzoyloxy-cyclopentano (2',l')]-octahydronaphthalene in the presence of a palladized carbon blackcatalyst and ethanol at a pH between about 4 to about 5, saponifying the3-ethoxy- 3 -methyl-l75- benzoyloxy 4 oxa-19-nor-A -[9fi]-androstene bythe action of an alkali metal hydroxide and recovering said3-ethoxy-3-methyl 4 oxa-19-nor-A -[9fl]-androsten- 175-01.

9. The process of producing 19-nor-ster0ids of the formula:

wherein R has the above-assigned meanings in the presence of a catalystand a lower alkanol solvent in an acidic media, cyclizing theoxa-steroids of the formula:

wherein R has the above-assigned meanings and R represents a lower alkylgroup, by the action of a strong mineral acid and recovering said19-nor-steroids.

10. The process of claim 9 wherein said strong mineral acid is aconcentrated aqueous solution of hydrochloric acid.

11. The process of claim 9 wherein said cyclization is effected in thepresence of an oxygenated organic polar solvent.

12. The process of claim 9 wherein the cyclization is effected at aconstant temperature below 25 C.

13. The process of producing 19 nor A -[9fl],[10ot]-androsten17fl-ol-3-one which comprises the steps of hydrogenating A-3-methyl-7-oxo-8-(3'-oxobutyl)-3,4-[3'- benzoyloxy-cyclopentano-(2',1)]octahydronaphthalene in the presence of a palladized carbon blackcatalyst and ethanol at a pH between about 4 to about 5, saponifying the3-ethoxy-3-methyl 17B benzoyloxy 4 oxa-19-nor- A -[9,B]-androstene bythe action of an alkali metal hydroxide, cyclizing the3-ethoxy-3-methyl-4-oxa-19-nor M -[9B]-androsten-17,B-ol by the actionof hydrochloric acid in the presence of a polar oxygenated organicsolvent at a temperature held constant at about 20 C. and recoveringsaid 19-nor-A -[9B],[10a]-androsten-17,8-ol-3- one.

14. The process of producing 19-nor A [9B],[10a]-androsten-l7/8-ol-3-one which comprises the steps of reacting a3-methy1-7-oxo-8-(3'-oxobutyl)-3,4-[3'-acyloxycyclopentano-(2',l')]decahydronaphthalene compound of the formula:

wherein R represents a radical selected from the group consisting ofhydrogen, lower alkyl, dihydropyranyl, tetrahydropyranyl and the acylradical of an organic carboxylic acid having from one to eighteen carbonatoms selected from the group consisting of alkanoic acids, alkenoicacids, cyclo-alkyl-alkanoic acids, phenylalkanoic acids, cycloalkanoicacids, phenylcarboxylic acids, halophenylcarboxylic acids,nitrophenylcarboxylic acids and naphthoic acid with an alkali metallower alkanolate, separating l9-nor-testosterone by chromatography, andrecovering said 19-nor-A -[9B],[10a]-androsten-17fi-ol-3- one.

15. The process of claim 14 wherein said 19-nor-testosterone isseparated by chromatography over silica gel with elution with methylenechloride containing increasing amounts of acetone up to 6% and the19-nor-A -[9 3], [10a] androsten 1715' 01 3-one is recovered from saidsilica gel by elution with methylene chloride containing 6% acetone.

References Cited in the file of this patent UNITED STATES PATENTS2,756,244 Djerassi et al. July 24, 1956

1. AN OXA-STEROID OF THE FORMULA: 